Thirty years of fluconazole therapy selects an azole-resistant Candida albicans isolate with a pre-adapted physiological, metabolic and structural state
- 1Department of Microbiology and Parasitology, Pharmacy Faculty, Complutense University of Madrid (UCM), 28040 Madrid, Spain
Abstract
Azole resistance in Candida albicans is traditionally attributed to alterations in drug targets and efflux mechanisms; however, how long-term antifungal exposure reshapes fungal physiology remains incompletely understood. Here, we characterize a fluconazole-resistant C. albicans clinical isolate (PUJ256) recovered from a patient with chronic mucocutaneous candidiasis after more than 30 years of continuous fluconazole therapy. Compared with the reference strain SC5314, the resistant isolate exhibited a clear fitness trade-off, with reduced filamentation and increased membrane vulnerability under basal conditions, yet enhanced fitness in the presence of fluconazole. Integration of phenotypic analyses with label-free quantitative proteomics revealed extensive metabolic remodelling, including coordinated regulation of central carbon metabolism, ergosterol biosynthesis and redox homeostasis. Notably, mitochondrial membrane potential was preserved in the resistant isolate under fluconazole stress, whereas the susceptible strain exhibited mitochondrial depolarization together with activation of MAPK signalling pathways. In addition, the resistant isolate displayed reduced susceptibility to phagocytosis under antifungal exposure, consistent with an increased capacity for persistence in the context of ongoing treatment. Collectively, our findings indicate that long-term azole resistance in C. albicans PUJ256 is associated with a stable, pre-adapted physiological state characterized by metabolic reprogramming and mitochondrial resilience. The prolonged antifungal exposure of this isolate provides a valuable opportunity to explore adaptative strategies that extend beyond canonical mechanisms, pointing to mitochondrial function and metabolic plasticity as potential targets for therapeutic intervention.
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BibTeX
@misc{parragiraldo2026thirty,
title = {{Thirty years of fluconazole therapy selects an azole-resistant Candida albicans isolate with a pre-adapted physiological, metabolic and structural state}},
author = {C. Parra-Giraldo and J. J. Estrada-Valbuena and Y. Vargas Casanova and I. Aldea and L. F. Clemente and C. Gil and R. Martinez-Lopez and L. Monteoliva},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.19.752827},
url = {https://www.biorxiv.org/content/10.64898/2026.09.19.752827v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Thirty years of fluconazole therapy selects an azole-resistant Candida albicans isolate with a pre-adapted physiological, metabolic and structural state
AU - C. Parra-Giraldo
AU - J. J. Estrada-Valbuena
AU - Y. Vargas Casanova
AU - I. Aldea
AU - L. F. Clemente
AU - C. Gil
AU - R. Martinez-Lopez
AU - L. Monteoliva
PY - 2026
DA - 2026/09/19
PB - bioRxiv
DO - 10.64898/2026.09.19.752827
UR - https://www.biorxiv.org/content/10.64898/2026.09.19.752827v1
AB - Azole resistance in Candida albicans is traditionally attributed to alterations in drug targets and efflux mechanisms; however, how long-term antifungal exposure reshapes fungal physiology remains incompletely understood. Here, we characterize a fluconazole-resistant C. albicans clinical isolate (PUJ256) recovered from a patient with chronic mucocutaneous candidiasis after more than 30 years of continuous fluconazole therapy. Compared with the reference strain SC5314, the resistant isolate exhibited a clear fitness trade-off, with reduced filamentation and increased membrane vulnerability under basal conditions, yet enhanced fitness in the presence of fluconazole. Integration of phenotypic analyses with label-free quantitative proteomics revealed extensive metabolic remodelling, including coordinated regulation of central carbon metabolism, ergosterol biosynthesis and redox homeostasis. Notably, mitochondrial membrane potential was preserved in the resistant isolate under fluconazole stress, whereas the susceptible strain exhibited mitochondrial depolarization together with activation of MAPK signalling pathways. In addition, the resistant isolate displayed reduced susceptibility to phagocytosis under antifungal exposure, consistent with an increased capacity for persistence in the context of ongoing treatment. Collectively, our findings indicate that long-term azole resistance in C. albicans PUJ256 is associated with a stable, pre-adapted physiological state characterized by metabolic reprogramming and mitochondrial resilience. The prolonged antifungal exposure of this isolate provides a valuable opportunity to explore adaptative strategies that extend beyond canonical mechanisms, pointing to mitochondrial function and metabolic plasticity as potential targets for therapeutic intervention.
ER -